Positive selection of T cells by self-agonists or agoniselection, is a novel thymic selection process that directs the development of specialized T lymphocytes with regulatory functions. This selection process occurs concurrently with negative selection of autoreactive conventional TCRa[unreadable] T cells and may be an important contributor in establishing self-tolerance. The total opposite outcome of the self-reactive immature thymocyte developing along the agonist selection pathway as opposed to the negative selection pathway suggests profound differences in the mediators that direct these two selection processes. The grant proposal aims at identifying and characterizing key factors that are crucial in this decision-making by examining the immature thymocytes, the selecting non-T cells and the crosstalk between these two cell types. [unreadable] Elucidating the conditions and requirements that lead to the specific selection of self-based regulatory T cells, as well as defining mechanisms that permit such selection, are fundamental for our understanding of how the immune system provides protection at all levels. New insights gained from this study will most certainly have important implications for understanding immune regulation and as a consequence for the development of new and improved immune-based therapies against cancer and autoimmune disorders. [unreadable] [unreadable] [unreadable] [unreadable]